Prostate cancer (PCa) is the most common male cancer and the second leading cause of cancer deaths in males (Jemal et al., 2003, Cancer Statistics. CA Cancer J. Clin. 53, 5-26). Although androgen deprivation is initially effective, it does not cure the disease, and invariably the tumor recurs in an androgen-independent form that is resistant to classical chemotherapy, and usually metastasizes primarily to the bone (Saitoh et al., 1984, Cancer 54, 3078-3084; Jacobs, 1983, Urology 21, 337-344). The molecular events underlying the progression of the disease have yet to be elucidated; however, it is clear that once the disease progresses it does not respond to the current array of chemotherapeutic agents (Koutsilieras and Tolis, 1985, Prostate 7, 31-39). There is, therefore, a clear need to develop new agents that kill hormone-independent prostate tumor cells and/or prevent their metastases.
A group of antitumor compounds collectively known as antitumor ether lipids (AELs) act by perturbing intracellular signaling pathways, leading to the killing of the cells (Arthur and Bittman, 1998, Biochim. Biophys. Acta 1390, 85-102; Bittman and Arthur, 1999, In Liposomes: Rational Design, A. S. Janoff, Ed., Marcel Dekker, New York, pp. 125-144). These compounds are long-lived analogs of the naturally occurring phospholipid, lysophosphatidylcholine (LPC). Insertion of two ether bonds into LPC in place of the usual two ester bonds gives an analog that is highly resistant to metabolism at sites other than in the vicinity of the phosphodiester linkage. AELs have the potential to deliver antitumor activity without any mutagenicity because, unlike many other anticancer agents, they do not interact directly with DNA. They possess cell-selective effects by inhibiting the proliferation and killing of cancer cells at concentrations that do not affect normal cells (Berdel, 1991, Br. J. Cancer 64, 208-211; Samadder and Arthur, 1999, Cancer Res. 59, 4808-4815). The prototype or gold standard AEL is known as 1-O-octadecyl-2-O-methyl-glycerophosphocholine (ET-18-OCH3), which inhibits a broad panel of tumor cell lines (Berdel et al., 1985, in Phospholipids and Cellular Regulation, Kuo, J. F., ed., Vol. 2, pp 41-73, CRC Press, Boca Raton, Fla.; Lohmeyer and Bittman, 1994, Drugs Future 19, 1021-1037; Houlihan et al., 1995, Med. Res. Rev. 15, 157-223; Mollinedo et al., 2004, Curr. Med. Chem. 2004, 11, 3163-3184) but it exhibits no known selectivity against specific cancer cell types.